Synthesis and biological activity of novel antibacterial quinazolines

Article abstract of DOI:10.1016/j.bmcl.2004.07.065

Novel quinazolines, having interesting antibacterial activity have been prepared, characterized and tested against a panel of susceptible and resistant Gram positive and Gram negative organisms.

Full text of DOI:10.1016/j.bmcl.2004.07.065

Bioorganic & Medicinal Chemistry Letters 14(2004) 5211–5213
Synthesis and biological activity of novel antibacterial quinazolines
b
b
Preet M. S. Bedi,a, V. Kumar and Mohinder P. Mahajan
*
aDepartment of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar-143005, Punjab, India
bDepartment of Applied Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India
Received 5 July 2004; accepted 21 July 2004
Available online 14August 2004
Abstract—Novel quinazolines, having interesting antibacterial activity have been prepared, characterized and tested against a panel
of susceptible and resistant Gram positive and Gram negative organisms.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
microwave condensation reactions of N-imidoyl imino-
phosphorane 4 with aldehydes 5. The iminophosphora-
nes 4 in turn were obtained from the corresponding
N-aryl benzamidine/guanidines 1 by their initial conver-
sion to N-chlorobenzamidine/guanidine 2 followed by
treatment with triphenylphosphine. The exposure of a
mixture of N-imidoyliminophosphorane 4 and aldehyde
5 to microwave radiation at a power of 300W for a per-
iod of 10–15min (5cycles of 3min each) resulted in the
excellent yields of quinozolines 6 (Scheme 1), which were
purified by column chromatography using a mixture of
ethyl acetate and hexane (1:10). The quinazolines so ob-
tained (6a–e) were characterized on the basis of analyt-
ical data and spectral evidences.
The rapid rise in bacterial resistance to the traditional
antibiotics such as Penicillins1 and tetracyclines2 has
encouraged a continuing search for new classes of com-
pounds with novel modes of antibacterial activity. The
quinolone antibacterials have emerged as an area of
immense interest because of their broad spectrum of
in vitro activity and their in vivo chemotherapeutic effi-
ciency.3–6 However, the current quinolones suffer from
some drawbacks such as limited activities against a
number of clinically important Gram positive such as
Streptococcus pneumonia, Streptococcus pyrogens, Sta-
phylococcus aureus and Enterococcus, low activity
against anaerobes and increasing quiolones resistance
among many pathogens.7 In view of the above, the de-
sign and synthesis of newer antimicrobials is an area
of immense significance and continues to attract the
attention of increasing number of medicinal chemists.
Quinazolines exhibit a wide range of activity such as
anthelmintic,8 antimicrobial,9–11 CNS depressant,12 neu-
roleptic,13 hypnotic14 and analgesic.15 In continuation of
our work on heterocycles16–20 with biological interest,
we wish to report here in some new title quinazolines
in order to study their antibacterial activities.
3. Antimicrobial activity
The antibacterial activity of all the synthesized com-
pounds was determined by agar well diffusion method
as recommended by the National Committee for Clini-
cal Laboratory Standards22–24 against Gram positive
microorganisms Bacillus subtilis MTCC 121, Bacillus
cereus MTCC 1272, Staphyloccocus aureus MTCC
1430, Enterococcus faecalis MTCC 439 and Gram nega-
tive microorganisms Escherichia coli MTCC 42, Pseudo-
monas aeruginosa MTCC 1034, Proteus vulgaris MTCC
744, Klebsiella pneumoniae MTCC 109 and Shigella son-
nei MTCC 2957 at 50lg/mL concentration, using di-
methyl sulfoxide (DMSO) as solvent. The bacteria
were subcultured on Mueller Hinton Agar medium.
Standard antibacterial ciprofloxacin was also screened
under similar conditions for comparison. Solvent con-
trol was also maintained under similar conditions. The
2. Chemistry
A novel series of 6-methyl-2-aryl/secondary amino-4-
aryl-quinazolines were conveniently prepared21 by the
Keywords: Quinazoline; Antibacterial; Resistant bacteria.
*
Corresponding author. Tel.: +91-183-2258802–09x3459; fax: +91-
183-2258819–20; e-mail: bedi_preet@yahoo.com
0960-894X/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.065

5212
P. M. S. Bedi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5211–5213
CH3
O
CH3
Dry
N-Cl
+
Dichloromethane
O
N
N
R
R
N
2
NH2
Cl
H
1
PPh3
CH3
CH3
10% NaOH
N
N
R
R
Cl
PPh3
N
N
PPh3
H
3
4
CH3
+
Microwave
R1CHO
300 Watts, 15 min
5
N
R
N
H
R1
Electrocyclization
N
N
R
R
Aromatisation
Ph3PO
+
N
HN
CH3
CH3
R1
R1
H
1
6
6a R = Ph ;
6b R = Ph ;
R = p-Me N-Ph
2
1
R = p-MeO-Ph
1
O
N
N
6c R =
; R = Ph
1
O
6d R =
; R = p-Me N-Ph
2
1
N
6e R =
; R = p-MeO-Ph
Scheme 1. Synthesis of 6-methyl-2-aryl/secondary amino-4-aryl-quinazolines.
Table 1. Antibacterial activity of compounds 6a–e against Gram positive and Gram negative bacterial strains
Bacterial Strain
Diameter growth of inhibition area (mm)
Compound
6
a
6
b
6
c
DMSO6
Cdiprofloxacin 6
e
B. subtilis MTCC 121
B. cereus MTCC 1272
S. aureus MTCC 1430
E. faecalis MTCC 439
P. aeruginosa MTCC 103418
P. vulgaris MTCC 744
K. pneumoniac MTCC 109
S. sonnei MTCC 2957
15
12
16
18
21
0
22
1413
11
15
19
16
0
17
0
12
12
16
22
17
19
16
0
0
21
16
12
16
19
16
15
0
18
17
19
15
17
15
18
19
20
18
20
19
18
20
21
0
0
0
19
18
21
22
16
E. coli MTCC 4
2
18
16
21
20
19
0
Petri dishes were incubated at 37°C for 48h to know the
bacterial growth inhibition developed around the hole
and was measured in millimetre for particular test solu-
tion with particular organism. The results are presented
in Table 1.
4. Results and discussion
It has been observed that the test compounds (6a–e)
exhibited interesting antibacterial activity, however with
a degree of variation. Results reveal that compounds 6d

P. M. S. Bedi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5211–5213
5213
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and 6e showed significant activity against K. pneumoniae
as compared to ciprofloxacin. Moreover, the introduc-
tion of p-methoxy phenyl group in compound 6b, de-
creases its antibacterial activity against Gram positive
and Gram negative bacterial strains. However com-
pound 6b did not show any activity against Gram posi-
tive S. aureus. Antibacterial data indicated that
compound 6c showed maximum activity against S. son-
nei as compared to the standard and exhibited signifi-
cant activity against E. faecalis and P. aeruginosa as
compared to ciprofloxacin. It is interesting to note that
by the introduction of morpholino and piperidino moi-
eties in compounds 6d and 6e, increases their antibacte-
rial activity against Gram positive and Gram negative
bacterial strains. Compound 6d was superior in action
against S. aureus, E. faecalis and K. pneumoniae over
the standard ciprofloxacin, where as compound 6e con-
taining piperidino moiety showed maximum activity
against K. pneumoniae as compared to ciprofloxacin.
Solvent DMSO did not show any antibacterial activity.
Therefore the results of antibacterial screening of com-
pounds revealed that quinazolines having morpholino
and piperidino heterocycles showed significant activity
comparable to standard drug against Gram positive
and Gram negative bacterial strains. The other chemical
moiety found to be favourable towards antibacterial
activity was p-dimethylamino phenyl followed by p-
methoxy phenyl in the quinazoline ring system.
16. Bedi, P. M. S.; Mahajan, M. P.; Kapoor, V. K. PDA J.
Pharm. Sci. Technol. 2003, 57, 109.
17. Bedi, P. M. S.; Mahajan, M. P.; Kapoor, V. K. Indian J.
Pharm. Sci. 2004, 66, 112.
18. Bedi, P. M. S.; Mahajan, M. P.; Kapoor, V. K. Bioorg.
Med. Chem. Lett. 2004, 14, 3821.
19. Jayakumar, S.; Kumar, V.; Mahajan, M. P. Tetrahedron
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20. Mohan, C.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett.
2004, 45, 6075.
21. Kumar, V.; Sharma, A.; Mahajan, M. P. Synth. Commun.
2004, 34, 49. The identity, and purity of all new
compounds established by IR, 1H NMR and mass spectral
data. For example, analytical data for 6a: Yield 75%, mp
212–213°C, mmax: 1590cmÀ1 (C@N), dH 2.58 (s, 3H, CH3);
3.33 (s, 6H, (NCH3)2); 6.91–6.96 (d, 2H, J = 10.0Hz,
ArH); 7.55 (m, 3H, ArH); 7.74–7.78 (d, 1H, J = 8.5Hz,
ArH); 7.90–7.95 (d, 2H, J = 10.0Hz, ArH); 8.07 (m, 2H,
ArH); 8.69 (m, 2H, ArH), M+ 339.
Acknowledgements
The authors are thankful to Departments of Chemistry
and Applied Chemistry, Guru Nanak Dev University,
Amritsar, for spectral analysis.
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